Utility of Animal Models of Pneumonia and Sepsis.

Infectious diseases, which often result in deadly sepsis or septic shock, represent a major global health problem. For understanding the pathophysiology of sepsis and developing new treatment strategies, reliable and clinically relevant animal models of the disease are necessary. In this review, two large animal (porcine) models of sepsis induced by either peritonitis or bacteremia are introduced and their strong and weak points are discussed in the context of clinical relevance and other animal models of sepsis, with a special focus on cardiovascular and immune systems, experimental design, and monitoring. Especially for testing new therapeutic strategies, the large animal (porcine) models represent a more clinically relevant alternative to small animal models, and the findings obtained in small animal (transgenic) models should be verified in these clinically relevant large animal models before translation to the clinical level.

BackgroundThe lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis.MethodsStool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient.ResultsMice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury.ConclusionsThe MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.

Neuropeptide Modulators of High Mobility Group Box 1 Secretion as Potential Therapeutic Agents for Severe Sepsis

We are seeing unparalleled advances in science and technology that have the potential to transform health and medicine. New technologies, data resources, research strategies, and delivery models are spurring advances in medical science and the delivery of care. However, notable challenges exist. The health system is strained by increasing demand and unsustainable costs. Politics has grown increasingly partisan, and trust in Congress remains low just as we enter a critical phase of uncertainty over healthcare reform. Concerns about the nation’s scientific competitiveness abound as research funding remains challenging. Part 2 is available on p 23 There is a need for a trusted advisor to provide objective and independent advice to researchers, health professionals, policy makers, and the public on matters related to health and biomedical science. As a result, the role of scientific academies, which bridge science and policy, has never been more important. Society can benefit enormously from the activities of an independent scientific academy with the directive to mobilize the best minds to advance knowledge and accelerate progress in science, medicine, and policy. Since its founding in 1970, the National Academy of Medicine (NAM; formerly the Institute of Medicine) has played that role. The NAM is 1 of the 3 academies that make up the National Academies of Sciences, Engineering, and Medicine (the National Academies) in the United States. Our history dates back to the time of the Civil War. In 1863, President Abraham Lincoln signed the National Academy of Sciences into existence under a charter that called for the organization to “whenever called upon by any department of the Government, investigate, examine, experiment, and report upon any subject of science or art…”1 As the scientific fields of engineering and medicine began to take more shape and importance, the National Academies of Engineering was born in 1963, …

Sepsis-associated encephalopathy is highly prevalent and has impact both in early and late morbidity and mortality. The mechanisms by which sepsis induces brain dysfunction include neuroinflammation, disrupted blood-brain barrier, oxidative stress, and microglial activation, but the cellular and molecular mechanisms involved in these events are not completely understood. Our objective was to determine the effects of microglial depletion in the early systemic and brain inflammatory response and its impact in phenotypes expression in an animal model of sepsis. Animals were subjected to CLP, and depletion of microglial cells was accomplished by administration of (Lipo)-encapsulated clodronate and microglial repopulation by doxycycline. Clod-lip treatment was effective in decreasing microglia density in the hippocampus of animals. Pro-inflammatory cytokines were increased in the CLP+PBS, and liposomes administration increased even further these cytokines mainly 7days, suggesting that microglial depletion exacerbates both local and systemic inflammation. In contrast, repopulation with doxycycline was able to revert the cytokine levels in both serum and cerebral structures on day 7 and 14 after repopulation. There were no differences in the correlation between M1 and M2 markers by real-time PCR, but immunohistochemistry showed significant increase in CD11b expression in CLP+PBS with greater expression in CLP + liposomes in the hippocampus. These results suggest that the depletion of microglia during severe sepsis development could be associated with early exacerbation of brain and systemic inflammation and repopulation is able to revert this condition, once a rapid neurological recovery is noticed until 7days after sepsis.

Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, is an emerging target in inflammation and oncology. To test my hypothesis that pan-TREM-1 and macrophage-restricted TREM-1 blockades may differ in their efficacy in cancer and other inflammatory diseases. Ligand-independent TREM-1 inhibitory peptides GF9 and GA31 (the latter in a form of macrophage-targeted lipopeptide complexes, GA31-LPC) were used as pan-TREM-1 and macrophage-restricted TREM-1 inhibitors, respectively, to test the hypothesis in multiple animal models of cancer, sepsis, pulmonary inflammation and fibrosis. In fully immunocompetent mice, GA31-LPC but not GF9 overcomes pancreatic cancer resistance to PD-L1 blockade and synergizes with immunotherapy. In PANC-1 xenograft-bearing athymic nude mice, GF9 and GA31-LPC both increase complete response rate and survival when combined with chemotherapy but exhibit opposing dependence on timing of treatment initiation. GF9 is effective only when given with but not after chemotherapy. In contrast, GA31-LPC is effective only when given after but not together with chemotherapy. Critical dependence of the therapeutic efficacy of TREM-1 blockade on the type of blocker and treatment timing was also observed in animal models of sepsis and acute lung injury but not fibrosis. This study provides the first evidence that pan-TREM-1 and macrophage-restricted TREM-1 blockades may strikingly differ in their therapeutic efficacy depending on the disease, timing of treatment initiation and the type and stage of inflammatory response. This opens new avenues for development of TREM-1-targeting strategies and leads to a new framework for the treatment of cancer and other inflammation-associated diseases.

Necrotizing fasciitis (NF) is a rare and extremely destructive soft tissue infection characterized by rapid progression and severe clinical manifestations. It can lead to serious complications and even death without prompt diagnosis and treatment. Despite advances in medical science, NF remains a major clinical challenge. This study analyzed 3381 NF-related research papers from the Web of Science Core Collection (WoSCC) database (1977-2024). We used text mining and bibliometric methods to research the number of papers, publishing institutions and countries, key authors, research hotspots, evolving trends, and other information, and to visualize the results. The analysis revealed a significant increase in publications, from fewer than 10 per year before 1990 to 228 in 2023. The United States, China, and Canada were the leading contributors, with the United States forming a core research network with Canada and the UK, while Chang Gung University in Taiwan, China, emerged as a key research hub in Asia. Early studies primarily focused on pathogens, whereas recent research has shifted toward treatment techniques and outcome prediction. High-frequency keywords like "mortality" and "diagnosis" reflect ongoing clinical challenges. Key unresolved issues include the diagnostic accuracy of the LRINEC score, optimal debridement timing, and health care disparities in resource-limited regions. The findings indicate a shift in NF research focus from etiology to clinical management and technological innovation. Future research should aim to refine diagnostic criteria, explore personalized treatments, and improve diagnostic capabilities in underserved areas. Interdisciplinary approaches, including information technology and materials science, are expected to drive NF research toward precision medicine.

Health and human behavior: areas of interest common to the social and medical sciences.

Sepsis and Sex: Can We Look Beyond Our Hormones?

Stearoyl lysophosphatidylcholine (LPC) has recently been proven protective against lethal sepsis by stimulating neutrophils to eliminate invading pathogens through an H2O2-dependent mechanism. Here, we demonstrate that stearoyl LPC, but not caproyl LPC, significantly attenuates circulating high-mobility group box 1 (HMGB1) levels in endotoxemia and sepsis by suppressing endotoxin-induced HMGB1 release from macrophages/monocytes. Neutralizing antibodies against G2A, a potential cell surface receptor for LPC, partially abrogated stearoyl LPC-mediated suppression of HMGB1 release. Thus, stearoyl LPC confers protection against lethal experimental sepsis partly by facilitating the elimination of the invading pathogens and partly by inhibiting endotoxin-induced release of a late proinflammatory cytokine, HMGB1.

To postulate reasons as to why the benefits seen with novel therapies in animal models of sepsis fail to translate to the clinical setting. MEDLINE searches and relevant book chapters. Thousands of preclinical trials performed over more than five decades have failed to find more than a handful of drugs and techniques that significantly improve outcomes in clinical sepsis. We review current concepts surrounding the variety of animal models used today, ranging from simple models of acute toxemia to more complex models of abdominal sepsis. Differences between animal and human populations are also examined including species, age, comorbidity, and the use of supportive therapies. Finally, we examine differences between preclinical and clinical trial design, and the potential for experimental and publication bias. Animal models of sepsis are still too heterogeneous with regard to type of insult, duration, and supportive therapy to be regarded as representative of the human condition. Using standardized animal models may eliminate some of the differences between animal and human studies, allowing a greater degree of translation.

Research assessing the changing epidemiology of infectious diseases in China after the implementation of new healthcare reform in 2009 was scarce. We aimed to get the latest trends and disparities of nationalnotifiable infectious diseases by age, sex, province, and season in China from 2010 to 2019. The number of incident cases and deaths, incidence rate, and mortality of 44 national notifiable infectious diseases by sex, age groups, and provincial regions from 2010 to 2019 were extracted from the China Information System for Disease Control and Prevention and official reports and divided into six kinds of infectious diseases by transmission routes and three classes (A-C) in this descriptive study. Estimated annual percentage changes (EAPCs) were calculated to quantify the temporal trends of incidence and mortality rate. We calculated the concentration index to measure economic-related inequality. Segmented interrupted time-series analysis was used to estimate the impact of the COVID-19 pandemic on the epidemic of notifiable infectious diseases. The trend of incidence rate on six kinds of infectious diseases by transmission routes was stable, while only mortality of sexual, blood-borne, and mother-to-child-borne infectious diseases increased from 0.6466 per 100 000 population in 2010 to 1.5499 per 100 000 population in 2019 by 8.76% per year (95% confidence interval [CI]: 6.88-10.68). There was a decreasing trend of incidence rate on Class-A infectious diseases (EAPC = -16.30%; 95%CI: -27.93 to -2.79) and Class-B infectious diseases (EAPC = -1.05%; 95%CI: -1.56 to -0.54), while an increasing trend on Class-C infectious diseases (EAPC = 6.22%; 95%CI: 2.13-10.48). For mortality, there was a decreasing trend on Class-C infectious diseases (EAPC = -14.76%; 95%CI: -23.46 to -5.07), and an increasing trend on Class-B infectious diseases (EAPC = 4.56%; 95%CI: 2.44-6.72). In 2019, the infectious diseases with the highest incidence rate and mortality were respiratory diseases (340.95 per 100 000 population), and sexual, blood-borne, and mother-to-child-borne infectious diseases (1.5459 per 100 000 population), respectively. The greatest increasing trend of incidence rate was observed in seasonal influenza, from 4.83 per 100 000 population in 2010 to 253.36 per 100 000 population in 2019 by 45.16% per year (95%CI: 29.81-62.33), especially among females and children aged 0-4 years old. The top disease with the highest mortality was still AIDs, which had the highest average yearly mortality in 24 provinces from 2010 to 2019, and its incidence rate (EAPC = 14.99%; 95%CI: 8.75-21.59) and mortality (EAPC = 9.65; 95%CI: 7.71-11.63) both increased from 2010 to 2019, especially among people aged 44-59 years old and 60 or older. Male incidence rate and mortality were higher than females each year from 2010 to 2018 on 29 and 10 infectious diseases, respectively. Additionally, sex differences in the incidence and mortality of AIDS were becoming larger. The curve lay above the equality line, with the negative value of the concentration index, which indicated that economic-related health disparities exist in the distribution of incidence rate and mortality of respiratory diseases (incidence rate: the concentration index = -0.063, p < 0.0001; mortality: the concentration index = -0.131, p < 0.001), sexual, blood-borne, and mother-to-child-borne infectious diseases (incidence rate: the concentration index = -0.039, p = 0.0192; mortality: the concentration index = -0.207, p < 0.0001), and the inequality disadvantageous to the poor (pro-rich). Respiratory diseases (Dec-Jan), intestinal diseases (May-Jul), zoonotic infectious diseases (Mar-Jul), and vector-borne infectious diseases (Sep-Oct) had distinct seasonal epidemic patterns. In addition, segmented interrupted time-series analyses showed that, after adjusting for potential seasonality, autocorrelation, GDP per capita, number of primary medical institutions, and other factors, there was no significant impact of COVID-19 epidemic on the monthly incidence rate of six kinds of infectious diseases by transmission routes from 2018 to 2020 (all p > 0.05). The incidence rates of six kinds of infectious diseases were stable in the past decade, and incidence rates of Class-A and Class-B infectious diseases were decreasingbecause of comprehensive prevention and control measures and a strengthened health system after the implementation of the new healthcare reform in China since2009. However, age, gender, regional, and economic disparities were still observed. Concerted efforts are needed to reduce the impact of seasonal influenza (especially among children aged 0-4 years old) and the mortality of AIDs (especially among people aged 44-59 years old and 60 or older). More attention should be paid to the disparities in the burden of infectious diseases.

Sepsis is a serious clinical problem involving complex mechanisms which requires better understanding and insight. Animal models of sepsis have played a major role in providing insight into the complex pathophysiology of sepsis. There have been various animal models of sepsis with different paradigms. Endotoxin, bacterial infusion, cecal ligation and puncture, and colon ascendens stent peritonitis models are the commonly practiced methods at present. Each of these models has their own advantages and also confounding factors. We have discussed the underlying mechanisms regulating each of these models along with possible reasons why each model failed to translate into the clinic. In animal models, the timing of development of the hemodynamic phases and the varied cytokine patterns could not accurately resemble the progression of clinical sepsis. More often, the exuberant and transient pro-inflammatory cytokine response is only focused in most models. Immunosuppression and apoptosis in the later phase of sepsis have been found to cause more damage than the initial acute phase of sepsis. Likewise, better understanding of the existing models of sepsis could help us create a more relevant model which could provide solution to the currently failed clinical trials in sepsis.

northover and subramanian([31][1]) reported in 1962 that treating dogs with aspirin, a prototypical nonsteroidal anti-inflammatory drug (NSAID), ameliorated the development of arterial hypotension after the injection of lipopolysaccharide (LPS). Subsequent to this early report, many other

30 Years of Women's Health Issues